High refractive index hydrogels and uses thereof

ABSTRACT

Optically transparent, high refractive index hydrogels are provided. Expansile hydrogel intraocular lenses are fabricated from the hydrogels by heating them above their elastic deformation temperatures and deforming them into an elongated configuration having at least one reduced dimension suitable for insertion through a small surgical incision. The lenses are allowed to cool in this configuration and retain the deformed shape prior to surgical implantation. Following implantation the lenses hydrate into an enlarged elastic form reassuming the original lens configuration of full capsule size.

This is a continuation-in-part of application Ser. No. 07/951,775 filedSep. 28, 1992 now U.S. Pat. No. 5,316,704.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to hydrogels. In one of its moreparticular aspects this invention relates to optically transparent highrefractive index hydrogels useful for fabricating articles such aslenses, especially intraocular lenses suitable for implantation usingsmall incision surgical techniques. More particularly, the presentinvention involves hydrogel intraocular lenses and methods for theirdeformation in a dehydrated state to a size which is sufficientlyreduced for their small incision implantation following cataractsurgery. Subsequent to surgical implantation, the deformed lenseshydrate within the ocular environment to full sized lenses.

2. Description of Related Art

Since the early 1940's optical devices in the form of intraocular lenseshave been utilized to replace the natural physiological crystallineocular lens in humans and other mammals. Typically, the intraocular lensis implanted within the ocular environment immediately after surgicallyremoving the natural lens which has become opaque or otherwise damagedby cataract formation or injury. For decades the most prevalentlyutilized materials for forming intraocular lenses were acrylates ormethacrylates and particularly polymethylmethacrylate, a rigid, glassypolymer.

More recently developed surgical techniques and improved instrumentationhave made it possible to remove the opaque or damaged natural lensthrough incision sizes as small as 2-3 mm. This contrasts sharply withearlier methods which involved forming incisions up to 9 or 10 mm inlength in order to remove the natural lens and insert the intraocularlens. Because small incision surgery is much less traumatic for patientsand decreases complications and healing time, this technique has becomethe method of choice for a large number of ophthalmic surgeons.

Since full-size intraocular lenses have diameters in the range of 8-13mm, far exceeding the 2-3 mm incision size, the standard rigidpolymethylmethacrylate lenses are not suitable for direct implantationthrough the reduced incision sizes. Thus, a number of differentintraocular lens designs and materials have been developed for use inconnection with small incision surgical techniques. One approachutilizes the concept of preparing lenses from elastomeric materials suchas silicones and thermoplastic polymers. Prior to surgically insertingthe elastomeric lens, the surgeon rolls or folds the lens so that it isreduced in size for passing into the eye through a smaller incision.Once placed within the eye, the lens unfolds or unrolls to its fullsize.

One problem associated with these elastomeric lenses is the possibilitythat permanent deformation or crease marks may occur when the lens isfolded or rolled. This is especially a concern at the center of the lensoptical zone where most of the rolling or folding deformation takesplace.

Another approach to providing a small incision intraocular lens issuggested in U.S. Pat. No. 4,731,079. This reference discloses anintraocular lens formed of a polymer having a softening (or glasstransition) temperature less than 42° C. and preferably about bodytemperature. The lens can be heated to above its softening temperatureand deformed by compression or elongation to reduce at least onedimension. Then, by cooling the lens at a temperature substantiallybelow its softening temperature, the lens will remain in the deformedconfiguration until it is warmed. Ophthalmic surgeons can implant thedeformed lens and once the lens warms to body temperature it returns toits original configuration.

A major problem associated with these intraocular lenses is therestricted number of polymers available for preparing the lenses.Polymethylmethacrylate has a glass transition temperature above 100° C.and thus cannot be used to form these lenses. Most acrylates andmethacrylates have similarly high glass transition temperatures. Thoughformulating the lenses with plasticizers will lower the glass transitiontemperature, the presence of plasticizers in intraocular lenses isgenerally unacceptable to most surgeons because of potential leachingproblems. Alternatively, water is a suitable plasticizer. However, onlysmall amounts of water, typically less than 10%, can be utilized in thepolymers to place the glass transition in the appropriate range. Thus,typical hydrogels which have much higher amounts of water are notsuitable for fabricating the deformable lenses.

An additional drawback with this suggested small incision intraocularlens is the added degree of surgical complexity required to deform thelens into its small incision configuration. The lenses are disclosed inU.S. Pat. No. 4,731,079 as being packaged in a form that requires theimplanting surgeon to warm, deform, and cool the lens immediately priorto its implantation. This procedure is considerably more involved thantraditional lens implantation techniques.

Another suggested approach for small incision lens implantation involvesimplanting hydrogel intraocular lenses in their smaller dehydratedstate. Once the implanted dehydrated lens is secured within the eye itreportedly hydrates and swells in the aqueous ocular environment. Asignificant problem associated with this approach is the large amount ofswelling required to produce an effective lens diameter. In order tofully swell the lens from a diameter of about 3 mm to about 6 mm thelens must swell 8 times by volume. This translates to a lens which is85% water. For larger full sized intraocular lenses the swell volume ismuch higher. Since most hydrogels are structurally very weak at thesehigh water contents, many surgeons are reluctant to implant them. Also,these high water content hydrogels have very low refractive indices,n_(D) ²⁰ of around 1.36 and in order to achieve suitable refractivepowers the hydrogel lens must be thicker in the optic portion. As aresult, a dehydrated hydrogel intraocular lens that will fit through adesirably small incision will not swell to a sufficiently large hydratedsize to effectively function as an intraocular lens. This problem iscompounded if larger, full size intraocular lenses that have opticdiameters greater than 6 mm are desired. In order to produce a hydratedlens having a sufficient optic diameter the dehydrated hydrogel lensmust be larger than desirable for a small incision implantationprocedure.

Alternatively, U.S. Pat. No. 4,919,662 suggests rolling or foldinghydrogel intraocular lenses in their elastic hydrated form, and thendehydrating the lenses at lower temperatures to fix the rolled or foldedlens configuration at a size suitable for small incision implantation.Once implanted, these lenses hydrate and swell to the original lensconfiguration. This method has the disadvantage of requiring thehandling of fully hydrated lenses during the deforming process.Unfortunately, hydrated lenses have relatively weak tear strengths andhandling the lenses causes frequent tearing damage.

U.S. Pat. No. 4,813,954 discloses expansile hydrogel intraocular lenseswhich are formed by simultaneously deforming and dehydrating hydrogelintraocular lenses prior to implanting the lenses in their dehydratedstate. Lenses subjected to this treatment swell to about 180% of theirreduced size. For example, lenses deformed or compressed to a diameterof 3.2 mm will swell to only about 5.8 mm. Thus, while providing someadvantages over simply implanting dehydrated lenses, the method andlenses described in U.S. Pat. No. 4,813,954 do not result in full sizedimplanted intraocular lenses of over 8 mm.

As those skilled in the art will appreciate, each of these prior artsmall incision lens approaches requires an intraocular lens havinggenerally circular, radially extending flange-type haptics as opposed totraditional filament style haptics. This is because the hydrogelmaterials do not have sufficient strength to stabilize the lens opticswhen shaped in conventional filament haptic forms. Thus, it is desirableto utilize lenses having full sized optics with diameters greater thanthe traditional 6 mm known in the art in order to provide lenses thatstably remain in position following implantation.

Accordingly, it is an object of the present invention to provideexpansile hydrogel intraocular lenses suitable for small incisionimplantation.

It is an additional object of the present invention to provide fullsized expansile hydrogel intraocular lenses and methods for theirproduction.

It is another object of this invention to provide high refractive indexhydrogels which are particularly adapted for use in producing lensessuch as soft contact lenses and expansile hydrogel intraocular lenses.

It is further an object of the present invention to provide methods forfabricating small incision expansile hydrogel intraocular lenses whichare suitable for packaging and storing in their reduced size.

SUMMARY OF THE INVENTION

The present invention accomplishes the above-mentioned objectives byproviding hydrogels which are optically transparent and have highrefractive indices. Such hydrogels can be used for preparing expansilehydrogel intraocular lenses as well as soft contact lenses and otherarticles. The expansile hydrogel intraocular lenses, in their dehydratedform, are suitably sized for small incision implantation. Unlike manyprior art expansile hydrogel intraocular lenses which, when dehydratedand suitably sized for small incision implantation, hydrate within theocular environment to undesirably small lens sizes, the intraocularlenses of the present invention hydrate and swell to full sizedintraocular lenses.

Generally speaking, the methods of the present invention involvedeforming dehydrated hydrogel intraocular lenses under elevatedtemperatures and then freezing the deformed lenses in their dehydratedconfiguration. The lenses retain their deformed configuration until theyare exposed to conditions under which the material becomes rubbery orelastic. These reformation conditions include exposing the lens toelevated temperatures or hydrating the lens material to form thehydrogel.

More particularly, the present invention provides methods forfabricating intraocular lenses suitably sized for small incisioninsertion by first providing a dehydrated intraocular lens having smalldehydrated dimensions and formed of hydrogel forming polymer having anelastic deformation temperature, preferably above ambient or roomtemperature. The next step includes deforming the dehydrated intraocularlens at a temperature at least as high as the elastic deformationtemperature to provide a deformed configuration with at least one of thedehydrated dimensions being sufficiently reduced to move the dehydratedand deformed lens through a small, typically 3 to 4 mm surgicalincision. Finally, allowing the deformed and dehydrated intraocular lensto cool to a temperature sufficiently below the elastic deformationtemperature freezes the deformed dehydrated intraocular lens in thissmall incision implantation deformed configuration.

Advantageously, once the lenses of the present invention are implantedwithin an aqueous physiological environment, the lenses hydrate andswell to effectively full sized lenses having diameters of over 6 to 8mm or more. Following hydration the lenses also become elastic andacquire shape memory characteristics due to the elevated amount of waterincorporated within the hydrogel material. This shape memorycharacteristic of the hydrated lenses makes it possible to perform thelens deformation processes using any of a variety of deformationtechniques, including radial compression and tensile elongation withoutimpacting the ability of the lenses to reform to their desiredpost-implantation configurations.

Exemplary hydrogel forming materials suitable for fabricating theexpansile intraocular lenses of the present invention may be anypolymer, copolymer, or polymer blend which is biocompatible and hydratesto a hydrogel having a hydrated equilibrium water content of at least20%. Such materials include copolymers formed of at least onehydrophilic or water soluble monomer and one hydrophobic monomer.Particularly preferred are cross-linked polymers and copolymers ofheterocyclic aromatic compounds such as 3-vinylpyridine,4-vinylpyridine, 4-vinylpyrimidine, vinylpyrazine and2-methyl-5-vinylpyrazine. Copolymers of two or more of these comonomersor copolymers of one or more of these comonomers with N-vinylimidazoleor other non-aromatic heterocyclic compounds cross-linked with, forexample, diethylene glycol diacrylate, tetraethylene glycol diacrylate,or 1,4-diacryloylpiperazine, have refractive indices, n_(D) ²⁰, rangingfrom 1.560 to 1.594 in the dry state. They hydrate to a hydratedequilibrium water content ranging from about 57% to 90%.

The relative amount of the various monomers used to produce the hydrogelforming materials will depend upon the desired final water content, thedesired refractive index, and the amount of material elasticity requiredto deform the lens above the desired elastic deformation temperature.The hydrogel materials also should have sufficient resiliency at theirdeformation temperatures to prevent permanent stretching or crackingduring and after the deforming process, as known in the art.

Similarly, the shapes and dimensions of intraocular lenses suitable fordeforming and implanting according to the present invention should besuch that the lenses will withstand the physical deformation process andhydrate to effective post implantation configurations.

For example, full sized disc shaped lenses having bi-convex,plano-convex, or concavo-convex cross-sectional configurations andgenerally smooth, circular peripheral contact areas are suitable due totheir generally symmetrical configuration. This configuration easilydeforms to the desired small incision shape and hydrates to anappropriate full size lens configuration with minimal insertion andplacement difficulty due to its symmetry. Similarly, disc shaped lenseshaving radially extending flange type haptics also may be utilized topractice the present invention. As those skilled in the art willappreciate, the outer periphery of the lens need not be continuous, aslong as it is reasonably symmetrical and of sufficient physicaldimension to provide a stable lens supporting structure. For ease ofmanufacturing, bi-convex full sized or radial flange haptic styles arepreferred.

Further objects, features and advantages of the expansile hydrogelintraocular lenses of the present invention, as well as a betterunderstanding thereof, will be afforded to those skilled in the art froma consideration of the following detailed explanation of exemplaryembodiments when taken in connection with the following drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs. 1a and b, respectively, illustrate an isometric view and anassociated cross-sectional view of an exemplary small incision, fullsized bi-convex, disc shape expansile hydrogel intraocular lens in itsdehydrated form prior to deformation.

FIGS. 2a and b, respectively, illustrate an isometric view and anassociated cross-sectional view of the exemplary small incision, fullsized bi-convex, disc shape expansile hydrogel intraocular lens of FIG.1 following deformation in accordance with the teachings of the presentinvention.

FIGS. 3a and b, respectively, illustrate an isometric view and anassociated cross-sectional view of the exemplary small incision, fullsized bi-convex, disc shape expansile hydrogel intraocular lens of FIGS.1 and 2 following hydration and swelling reformation into its full sizedpost-implantation configuration.

FIG. 4 is a graphical representation of the hydration characteristics ofan exemplary, 2,3-dihydroxypropylmethacrylate (DHPMA) lens formingpolymer illustrating the percent water up-take at room temperature overtime and the equilibrium water content upon hydration.

FIG. 5 is a graphical representation of the hydration characteristics ofan exemplary tetraethylene glycol diacrylate (TEGDA) cross-linkedN-vinylpyrrolidone (NVP) lens forming copolymer illustrating the percentwater up-take at room temperature over time and the equilibrium watercontent upon hydration.

FIG. 6 is a graphical representation of the hydration characteristics ofan exemplary cross-linked N-vinylsuccinimide (NVS) lens formingcopolymer illustrating the percent water up-take at room temperatureover time and the equilibrium water content upon hydration.

FIG. 7 is a graphical representation of the hydration characteristics ofan exemplary NVP and N-(3-picolyl)methacrylamide (PIMA) lens formingcopolymer illustrating the percent water up-take at room temperatureover time and the equilibrium water content upon hydration.

FIG. 8 is a graphical representation of the hydration characteristics ofan exemplary vinylpyrazine (VPZ) lens forming polymer illustrating thepercent water up-take at room temperature over time and the equilibriumwater content upon hydration.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Broadly, the present invention provides methods for deforming orsubstantially reducing the size of shaped articles formed of polymerwhich is capable of subsequent swelling and expansile reformation insuitable fluids. These shaped polymeric articles can be deformed to asubstantially reduced size while in the polymer's dry unswelled stateknown as its xerogel form. Then, once exposed to an appropriate fluid,the polymeric articles swell in all dimensions, returning to theiroriginal shape and a substantially increased size.

Because the methods of the present invention advantageously providereduced sized deformed articles which swell to larger reformed volumes,they are particularly useful for preparing expansile intraocular lensesfor implanting within the eye using small incision surgical techniques.The advantageously high swelling ratios allow the lenses to beconfigured for small incision insertion into the eye where the lenseshydrate and swell to full sized hydrogel intraocular lenses. Thoseskilled in the art will appreciate, however, that the methods of thepresent invention are suitable for other uses where polymeric articlescapable of swelling to larger dimensions have utility.

The present invention is based upon the discovery that the hydratedelastic properties and shape memory properties of polymers which swellin the presence of fluids can be utilized to prepare deformablepolymeric articles having specific, reduced dimensions yet which providelarge swell volumes and shape reformation characteristics. That is, thepresent invention involves exposing a hydrogel article in its dehydratedstate to thermal conditions under which the dehydrated article iselastic, and then deforming and freezing the article in its deformedconfiguration. The result is a dehydrated and deformed polymericarticle, which, following hydration, displays substantially increasedswell volumes and dimensions.

More particularly, an exemplary embodiment of the present inventionprovides methods for fabricating intraocular lenses suitably sized forsmall incision insertion by first providing a dehydrated intraocularlens having at least one desirably small dehydrated dimension and formedof hydrogel forming polymer having an elastic deformation temperature.Preferably, the elastic deformation temperature is sufficiently high tobe above ambient or room temperature. The next step includes deformingthe dehydrated intraocular lens at a temperature at least as high as theelastic deformation temperature to provide a deformed configuration withat least one of the dehydrated dimensions being sufficiently reduced tomove the dehydrated and deformed lens through a 3 to 4 mm surgicalincision. Finally, allowing the dehydrated and deformed intraocular lensto cool to a temperature sufficiently below the elastic deformationtemperature freezes the deformed dehydrated intraocular lens in itsdeformed configuration. The resulting expansile small incisionintraocular lens is capable of swelling to a full sized hydrogelintraocular lens upon exposure to an aqueous environment such as anocular physiological environment; yet, in its deformed state theintraocular lens has beneficially small dimensions suitable forcontemporary small incision implantation techniques.

In accordance with the processes of the present invention, deforming thedehydrated intraocular lenses can be accomplished by any method whichreduces the profile of the lens in at least one dimension. For example,a dehydrated lens can be compressed by applying pressure from its outercircumference inward. Vise clamps fitted with circular shaped fixturescan be utilized for this purpose. This method results in a reducedcross-sectional lens diameter and increased lens thickness, preferablyon the order to 1 to 3 mm.

An alternative deforming method includes elongating or stretching thelens using tensile forces. Tweezers, forceps or other clamping tools canbe utilized for this purpose wherein the lens is grasped atdiametrically opposed positions about its periphery and stretched intoan elongated, lozenge shape having an appropriately reducedcross-sectional diameter. Alternative deforming methods include rollingor folding the lenses to reduce their cross-sectional profiles.Exemplary methods for rolling or folding include those used to roll andfold elastomeric lenses such as those formed of silicones, as known inthe art.

In order to deform the dehydrated lenses of the present inventionwithout cracking or otherwise damaging the lens, the deforming step isperformed at a temperature at which the dehydrated lens is sufficientlyelastic for non-destructive deformation. More particularly, articlesprepared from xerogel polymers can be deformed and reduced in size to adeformed configuration without damage when the deforming step isperformed at temperatures which exceed the elastic deformationtemperature of the polymer used. For many polymers, the elasticdeformation temperature is in the same temperature region as thepolymer's glass transition temperature, the temperature at which thepolymer transforms from a glassy state to an elastic state. For purposesof the present invention, however, the deformation temperature and glasstransition temperature can be separate thermodynamic temperatures.Within the temperature region between the deformation temperature andthe polymer's degradation temperature, the polymer can be deformedthrough the controlled application of external force. However, if theexternal force is removed, the polymer will elastically return to itsoriginal configuration unless treated in accordance with the teachingsof the present invention.

Those skilled in the art will appreciate that glass transitiontemperatures and polymer deformation temperatures vary from polymer topolymer. Typically, polymers increase in elasticity as the temperatureincreases above their glass transition temperatures. Accordingly, asdiscussed below, suitable elastic deformation temperatures should beseparately determined for each type of hydrogel forming polymer used inthe practice of the present invention. Preferably, the elasticdeformation temperature is above ambient temperatures and, morepreferably, above about 55° C. Those skilled in the art will appreciatethat elastic deformation temperatures which are above the range of about55° C. allow deformed articles which are exposed to elevatedtemperatures during shipping and storage to maintain their deformedconfiguration under ambient conditions. This is because the deformedarticle is subjected to temperatures below those temperatures whichcause the deformed article to become elastic.

In accordance with the present invention, allowing the deformeddehydrated article, for example, the intraocular lens, to cool to asuitable temperature below its elastic deforming temperature prior toremoving the compression or elongation forces effectively freezes thedeformed article in its deformed configuration. At this lower freezingtemperature the dehydrated article does not require application ofexternal forces to remain in the deformed configuration. In fact, oncecooled below the elastic deformation or freezing temperature, thedeformed articles remain deformed until exposed to conditions underwhich the polymer is again elastic, at which point the articles returnto their original shapes.

Typically, a suitable freezing temperature is a temperature below theglass transition temperature of the hydrogel forming polymer in itsxerogel form. At the lower temperature the polymer is in its plasticform as opposed to its higher temperature elastic form. In this plasticform the article has little resilience. This contrasts with the elasticform where the deformed article returns to its original shape once thedeformation forces are removed.

For purposes of practicing the present invention, and as mentionedabove, preferred temperatures for freezing the deformed articles intheir deformed configuration are in the range of ambient temperatures.Thus, allowing the heated deformed article to cool below about 30° C.provides a deformed article which is frozen in its deformedconfiguration. This allows the deformed articles of the presentinvention to retain their deformed configuration during storage andshipping without refrigeration or special considerations.

The articles and the hydrogel forming polymers utilized to form thearticles should meet certain physical characteristics so that thearticles are not damaged during the deforming processes of the presentinvention. The polymer xerogels or dehydrated forms should havesufficient elasticity at their deforming temperatures to allow thearticles to be deformed to sufficiently reduced sizes without breakingor cracking. Preferably, the material from which the article is formedis not elastic at ambient temperatures, thus allowing the deformedarticles to remain in a deformed configuration during storage andshipping. Additionally, where the hydrogels are used to fabricateintraocular lenses, suitable polymeric materials for practicing thepresent invention will hydrate and swell to form hydrogels havingsufficient water to exhibit elastic characteristics and shape memoryproperties at body temperatures, thereby enabling the lenses to reformto sizes, shapes and configurations effective for their intendedfunctions as intraocular lens implants.

Any of the polymers currently utilized to form hydrogel intraocularlenses are suitable hydrogel forming polymers for purposes of practicingthe present invention. Thus, commercially available hydrogel intraocularlenses can be deformed according to the processes of the presentinvention and then implanted utilizing small incision methodologies.Additionally, many other hydrogel forming polymers and copolymers havingproperties appropriate for fabricating hydrogel lenses are suitablehydrogel forming polymers for practicing the present invention.

Generally, hydrogel forming polymers are cross-linked polymers of watersoluble or hydrophilic monomers or copolymers of water soluble and waterinsoluble monomers. Because of their importance in the field ofbiomaterial and agriculture, hydrogels and processes for their formationare well documented in the literature. Typical hydrogel materialsinclude homopolymers and copolymers of acrylamides, methacrylamide,acrylate and methacrylate esters having at least one hydroxyl group onthe side chain, such as 2-hydroxyethyl methacrylate, hydroxyethoxyethylmethacrylate, hydroxydiethoxy methacrylate, 2,3 dihydroxypropylmethacrylate, and glycerol methacrylate. Other suitable hydrogel formingpolymers include polymers and copolymers of monomers such asmethoxyethylethoxyethyl methacrylate, methoxydiethoxyethyl methacrylate,methoxyethyl methacrylate, methacrylic acid, divinyl sulfone, vinylmethyl sulfone, vinyl alcohol, and vinyl acetate. Heterocyclic compoundssuch as N-vinyl-2-pyrrolidone and related N-alkenyl-2-pyrrolidones,N-vinyl carbazole, N-vinyl succinimide, N-(3-picolyl) methacrylamide,and N-vinylimidazole are also suitable monomers.

A preferred class of hydrogel forming polymers includes cross-linkedpolymers and copolymers of heterocyclic aromatic compounds such as3-vinylpyridine, 4-vinylpyridine, 4-vinylpyrimidine, vinylpyrazine and2-methyl-5-vinylpyrazine. Copolymers of two or more of these comonomersor copolymers of one or more of these comonomers with N-vinylimidazoleor other non-aromatic heterocyclic compounds cross-linked with, forexample, diethylene glycol diacrylate, tetraethylene glycol diacrylate,or 1,4-diacryloylpiperazine, have refractive indices, n_(D) ²⁰, rangingfrom 1.560 to 1.594 in the dry state. They hydrate to a hydratedequilibrium water content ranging from about 57% to 90%. In the nitrogencontaining heterocyclic aromatic compounds the nitrogen atoms imparthydrophilicity via hydrogen bonding with water molecules, while thedelocalization of the π electrons of the aromatic rings contributes tothe high refractive indices of the copolymers.

As pointed out above, high water content hydrogels generally have verylow refractive indices, n_(D) ²⁰. It is, therefore, unexpected to findthat a cross-linked polymer of vinylpyrazine, for example, with a veryhigh equilibrium water content of 89.2% has a refractive index of 1.594.By using the high refractive index hydrogels of this invention it ispossible to provide higher refractive power in a lens or other articlewith a much thinner optic portion than by using the low refractiveindex, high water content hydrogels previously available. It will beappreciated by those skilled in the art that the hydrogels of thepresent invention can be tailored to provide a wide range of refractiveindices, n_(D) ²⁰, upwards of about 1.560 and hydrated equilibrium watercontents ranging from about 20% to 90% in order to accommodate a varietyof utilities.

The hydrogels of the present invention may also include from about 0.1wt % to about 10 wt % ultraviolet (UV) radiation absorbing compounds.Preferably, the UV absorbing compound is copolymerizable with themonomer forming the hydrogel polymer, thus becoming part of the finalpolymer or copolymer. This feature assures that the hydrated hydrogel isoptically clear, and assures that the UV absorbing compound does notleach or migrate from the article fabricated from the hydrogel, forexample, from an implanted lens.

As noted above, hydrogel materials may not be suitable for formingintraocular lens haptics in traditional radial filament configurationsdue to their flexibility. Accordingly, while it is contemplated as beingwithin the scope of the present invention to utilize lenses havingconventionally shaped haptics, it is preferred that the haptics beconfigured to account for the physical and structural properties of thehydrogel materials. Thus, as illustrated in FIG. 1, an exemplary lensconfiguration suitable for practicing the present invention is abi-convex disc shaped lens, generally indicated by reference 10.Exemplary lens 10 is shown in its dehydrated state having dimensionalcharacteristics sufficiently reduced from that of its intended,post-implantation hydrated configuration. Thus, the outercircumferential periphery 14 of the lens 10 is intended to position lens10 within the capsular bag of the eye following implantation andhydration. Those skilled in the art will appreciate that periphery 14can be provided with radially extending flanges or blade type haptics(not shown) if desired. In such a configuration, lens 10 would functionas the optic portion of an intraocular lens having a larger overalldiameter. Thus, full size hydrogel intraocular lens implants havingoptic diameters of up to 10 mm and overall diameters of up to 13 mm ormore can be produced utilizing the techniques of the present inventionso that these lenses can be effectively reduced in size and implantedutilizing small incision surgical techniques.

More particularly, FIGS. 1-3 illustrate exemplary lens configurationssuitable for practicing the fabrication and deformation methods of thepresent invention. FIGS. 1a and b illustrate the configuration ofexemplary lens 10 in its dehydrated, reduced dimension form. FIGS. 2aand b illustrate an exemplary deformed configuration of lens 10 havingat least one dimension sufficiently small to enable the lens to beinserted through a typical small incision lens implantation procedure.FIGS. 3a and b illustrate the post-implantation hydrated dimensions andconfigurations of lens 10.

In FIG. 1a lens 10 is shown as a circular, bi-convex lens in itsdehydrated configuration having an exemplary diameter 12 ranging fromapproximately 4 to 7 mm. As shown in FIG. 1b an exemplarycross-sectional thickness 16 for lens 10 ranges from approximately 2 to4 mm.

In accordance with the teachings of the present invention, lens 10 maybe deformed in its dehydrated state into an elongated configuration asillustrated in FIG. 2a. Thus, by warming dehydrated lens 10 above itselastic deformation temperature, grasping opposite edges ofcircumferential periphery 14 with suitable tools and pulling, lens 10may be pulled into the lozenge shape of FIG. 2a having a long dimension18 on the order of 8 to 10 mm and, as illustrated in FIG. 2b, across-sectional width 20 of approximately 2 to 4 mm and across-sectional height 22 of approximately 2 to 3 mm. As noted above,the lozenge shape illustrated in FIG. 2a can also be produced byapplying compressive forces across diameter 12 or through rolling andfolding. Regardless of the deformation technique, before the deformingforces are removed lens 10 is allowed cool below its elastic deformationtemperature to its freezing temperature. This can be accomplished byplacing lens 10 in an appropriately configured fixture such as a tubularholder and allowing the heated lens to cool prior to removal from theholder or clamps.

As is readily apparent from FIGS. 2a and b, in its deformedconfiguration lens 10 can be inserted through an ocular incision on theorder of 3 to 4 mm in length by presenting the reduced cross-sectionaldimensions of the elongated, deformed lens and sliding the lens throughthe incision. Coating lens 10 with a viscoelastic material mayfacilitate this movement through the ocular incision. Advantageously,the deformed lens 10 illustrated in FIG. 2a and b is capable ofminimizing the possibility of decentration once it is inserted in theocular capsular bag. The ocular capsular bag has a general oval shapeand the average size of the natural human lens is about 9.6 mm× 4.3 mm.The elongated shape of deformed lens 10 causes the lens to orient itselfwithin the bag in alignment with the shape of the capsular bag.Additionally, the length of the elongated dimension acts as an anchor tosecure the expansile deformed lens within the ocular capsular bag duringthe hydration process.

Following implantation lens 10 is allowed to hydrate and swell to anenlarged, full sized configuration as illustrated in FIGS. 3a and b. Asshown in FIG. 3a, hydrated lens 10 has returned to its circularconfiguration and has enlarged to an expanded diameter 24 on the orderof 8 to 10 mm. Similarly, as shown in FIG. 3b, the expandedcross-sectional thickness 26 of hydrated lens 10 is significantly largerthan that of dehydrated cross-sectional thickness 16 and ranges on theorder of 4 to 5 mm in this exemplary embodiment.

Thus, FIGS. 1-3 clearly demonstrate the dramatic reduction in at leastone dimension of an expansile hydrogel lens that may be produced throughthe method of the present invention to provide a lens implant that canbe inserted through a small incision surgical technique, yet will expandto a full size hydrated implant that reforms to its originalconfiguration. By artfully combining the elasticity of the dehydratedlenses at elevated temperatures with their elastic memory behaviorfollowing hydration in combination with their swelling characteristics,the present invention provides full sized expansile hydrogel lenses thatcan be inserted through small surgical incisions.

It is also an aspect of the present invention to provide associatedprocesses for surgically implanting such small incision intraocularlenses. An exemplary implantation process includes the steps ofproviding an ocular incision of less than about 4 mm in length andinserting such a deformed expansile intraocular lens through the ocularincision. Following insertion the deformed lens is allowed to hydrateand swell to an enlarged, full sized hydrogel intraocular lens havingthe configuration of the original reduced size lens only with enlargeddimensional characteristics.

Unlike prior art small incision procedures for implanting expansileintraocular lenses which are restricted to less than full sized hydrogellenses, the processes of the present invention provide for theimplantation of full sized hydrogel lenses. This is made possiblebecause the processes of the present invention utilize both thehydration swelling and elastic memory characteristics of hydrogels.Moreover, the present invention contrasts with prior art methods forpreparing deformed polymeric intraocular lenses for small incisionimplantation in that prior art processes depend upon only thetemperature related elastic deformation properties of polymers. Asmentioned above, the prior art deformation processes occur atphysiological temperatures and elastic recovery occurs at physiologicaltemperatures.

Thus, materials suitable for deforming according to prior art methodsmust have deformation temperatures which are close to physiologicaltemperatures and freezing temperatures which are just belowphysiological temperatures. In any case, the maximum materialdeformation temperature is only slightly above 40° C. for these priorart processes. Generally, polymers having higher plasticizer contentpossess lower elastic deformation temperatures. Further, waterincorporated in the polymer matrix of hydrogels acts as a plasticizer,effectively maintaining a low elastic deformation temperature comparedwith the xerogel state of the polymeric material. Typical hydrogels usedto fabricate ophthalmic lenses have elastic deformation temperatureswhich are substantially below physiological temperatures. Accordingly,these hydrogels are not suitable for processing according to prior artdeformation procedures since they do not remain deformed withoutexternal forces at room temperatures.

As mentioned above, in addition to being elastic at temperatures abovethe elastic deformation temperature, suitable hydrogel polymers forpracticing the present invention are elastic in their hydrated form.Thus, by simply hydrating the deformed hydrogel intraocular lenses ofthe present invention, even at temperatures less than the elasticdeformation temperature, the lenses return to an elastic state andrecover their original configuration. This is in addition to thesubstantial size increase attributed to the hydrating and swellingaction.

The following examples are offered as being illustrative of theprinciples of the present invention and not by way of limitation.

EXAMPLE 1

A total of ten different copolymers and homopolymers were prepared andevaluated for use as exemplary hydrogel forming materials of the presentinvention. Table I illustrates the proportions of each component of thepolymerization mixture and presents comments relating to the polymer.Each polymerization procedure was carried out by first mixing theappropriate amounts of the monomer, comonomer, cross-linker andpolymerization initiator as indicated in the first column of Table I.Then each mixture was transferred to an ampoule which was pre-treatedwith a silicone grease mold releasing agent. Each ampoule and mixturewas then attached to a vacuum system and cooled with liquid nitrogen.After the mixture was frozen by the liquid nitrogen, the mixture wasevacuated by turning on the vacuum system. Once a constant pressure wasachieved, the vacuum system was turned off and the mixture was allowedto thaw by warming the ampoule in a water bath. This freeze-thaw cyclewas repeated three times in order to provide sufficient mixturedegassing. Finally, each mixture and ampoule were sealed under vacuum oran inert gas such as nitrogen or argon and polymerized. Thepolymerization temperatures and time periods varied with the particularmonomers and comonomers in the polymerization mixture as indicated inthe second column of Table I.

The abbreviations utilized in Table I are identified in Table II,immediately following.

                                      TABLE I                                     __________________________________________________________________________    MONOMERS AND                                                                             POLYMERIZATION                                                     COMPONENTS CONDITIONS  PROPERTIES                                                                              COMMENTS                                     __________________________________________________________________________    (1)                                                                           7 ml DHPMA  60° C./60 h                                                                       Clear colorless                                                                         Slow                                         35 μl EGDMA                                                                           110° C./24 h                                                                       solid; clear in                                                                         hydration                                    7 mg AIBN              swollen state                                          (2)                                                                           7.96 ml NVP                                                                               60° C./63 h                                                                       Clear colorless                                                                         Rapid                                        40 μl TEGDA                                                                           120° C./30 h                                                                       solid; clear in                                                                         hydration                                    8 mg AIBN              swollen state                                          (3)                                                                           7.92 ml NVP                                                                               60° C./63 h                                                                       Clear colorless                                                                         Rapid                                        80 μl TEGDA                                                                           120° C./30 h                                                                       solid; clear in                                                                         hydration                                    8 mg AIBN              swollen state                                          (4)                                                                           9.8 ml NVP  60° C./63 h                                                                       Clear colorless                                                                         Rapid                                        0.2 ml TEGDA                                                                             120° C./30 h                                                                       solid; clear in                                                                         hydration                                    ml AIBN                swollen state                                                                           IOLs made                                    (5)                                                                           3.96 g NVS  50° C./48 h                                                                       Clear colorless                                                                         Low water content;                           40 mg TEGDA                                                                               80° C./48 h                                                                       solid; clear in                                                                         intermediate                                 4 mg AIBN  100° C./6 h                                                                        swollen state                                                                           hydration rate                               (6)                                                                           5.54 g NVP  50° C./60 h                                                                       Clear colorless                                                                         Intermediate                                 1.39 g PIMA                                                                               80° C./24 h                                                                       solid; clear in                                                                         hydration rate                               70 mg TEGDA                                                                              120° C./6 h                                                                        swollen state;                                         7 mg AIBN              water content 89%                                      (7)                                                                           7.5 g NVP   50° C./40 h                                                                       Clear slightly                                                                          Rapid                                        7.5 g NVI   80° C./96 h                                                                       yellow solid; clear                                                                     hydration                                    150 mg TEGDA           in swollen state;                                      15 mg AIBN             water content 94%                                      (8)                                                                           2.4 g NVI   60° C./48 h                                                                       Clear slightly                                                                          Rapid                                        0.6 g 4VP  120° C./12 h                                                                       yellow solid; clear                                                                     hydration                                    60 μl TEGDA         in swollen state;                                      3 mg AIBN              water content 61%                                      (9)                                                                           7.5 g NVI   60° C./48 h                                                                       Clear slightly                                                                          Rapid                                        2.5 g 4VP  120° C./24 h                                                                       yellow solid; clear                                                                     hydration                                    60 μl TEGDA         in swollen state;                                      10 mg AIBN             water content 63%                                      (10)                                                                          7.5 g NVI   60° C./48 h                                                                       Clear slightly                                                                          Rapid                                        2.5 g 4VP  120° C./24 h                                                                       yellow solid; clear                                                                     hydration                                    100 μl TEGDA        in swollen state;                                      10 mg AIBN             water content 61%                                      __________________________________________________________________________

                  TABLE II                                                        ______________________________________                                        COMPONENTS           ABBREVIATION                                             ______________________________________                                        2,3-Dihydroxypropyl  DHPMA                                                    methacrylate                                                                  Ethylene glycol dimethacrylate                                                                     EGDMA                                                    2,2'-Azobisisobutyronitrile                                                                        AIBN                                                     N-Vinylpyrrolidone   NVP                                                      Tetraethylene glycol diacrylate                                                                    TEGDA                                                    N-Vinylimidazole     NVI                                                      N-(3-Picolyl) methacrylamide                                                                       PIMA                                                     4-Vinylpyridine      4VP                                                      N-Vinylsuccinimide   NVS                                                      ______________________________________                                    

The hydration characteristics and equilibrium water contents weredetermined for five of the polymers and copolymers identified in TableI. Water uptake profiles were determined by placing equal size blanks ofeach polymer or copolymer in deionized water and periodically weighingeach sample to determine the weight increase caused by water uptake.These results were plotted to determine a water uptake profile andequilibrium hydration water content as illustrated in FIGS. 4 through 7.FIG. 4 illustrates the water uptake profile of an exemplary DHPMApolymer identified as polymer 1 in Table 1. Water content was measuredover a period of 14 days of hydration and stabilized at an equilibriumwater content of approximately 45% to 48% following 4 days of hydration.FIG. 5 illustrates a much faster water uptake profile of a TEGDAcross-linked NVP polymer identified as polymer 4 of Table I occurringover a 7 hour period. An equilibrium water content of approximately 85%was achieved in 6 hours. A 40 hour water uptake profile of cross-linkedNVS polymer (polymer 5 of Table I) is illustrated in FIG. 6 and a 24hour water uptake profile of a cross-linked polymer of NVP and PIMA(polymer 6 of Table I) is illustrated in FIG. 7.

The following example illustrates the deformation method of the presentinvention utilizing a cross-linked N-Vinylpyrrolidone polymer.

EXAMPLE 2

In order to demonstrate the feasibility of the deformation method of thepresent invention a full sized expansile intraocular lens was preparedfrom polymer 4 of Table I by polymerizing a mixture of N-vinylpyrrolidone and 2 wt % tetraethyleneglycol diacrylate with an AIBNinitiator. The same general procedure described in Example 1 wasutilized to prepare the mixture filled ampoule for polymerization andthe polymerization process included a 72 hour cycle at 60° C. and a 48hour cycle at 120° C. After the polymerized material was cooled theampoule was broken open and the resulting polymer rod was cut intoblanks. Each blank was then machined to an expansile intraocular lens inits dehydrated state. These blanks generally corresponded to theexemplary lens configuration 10 illustrated in FIGS. 1a and b. Themachined dehydrated lenses had diameters 12 ranging from approximately4.5 to 7.1 mm and cross-sectional thicknesses 16 ranging fromapproximately 2.3 to 3.6 mm.

Exemplary lenses were deformed by heating a water bath to 60° C. andplacing a beaker of heptane in the water bath. The lenses were immersedin the warm heptane for approximately 10 seconds and simultaneouslyfolded with a pair of tweezers. The folded lenses were then removed fromthe heptane and inserted into 1/16 inch I.D. silicone tubes. The tubeand folded lenses were then immersed in the warm heptane for 10-20seconds. The tubes and lenses were removed from the heptane andimmediately rolled and squeezed between two fingers, compressing thelenses into tightly folded and elongated shapes. The elongated lensesand tubes were allowed to cool to room temperature and then the lenseswere removed from the tubes. At room temperature the lenses remained intheir elongated state and had a configuration similar to thatillustrated in FIGS. 2a and b. The long dimension 18 ranged fromapproximately 8 to 13 mm, the cross-sectional width 20 ranged fromapproximately 2 to 4 mm, and the cross-sectional height 22 ranged fromapproximately 1.8 to 3.0 mm.

Each lens was immersed in physiologically buffered aqueous solutions for8-48 hours and allowed to hydrate to an equilibrium water content ofabout 85% by weight. The lenses were observed to expand and reform tothe original configuration as illustrated in FIGS. 3a and b. Theenlarged reconfigured hydrated lenses had expanded diameters 24 rangingfrom approximately 8.5 to 9.5 mm and expanded cross-sectionalthicknesses 26 of approximately 4.5 mm.

The following example illustrates the use of a cross-linked copolymer ofN-vinylimidazole and 4-vinylpyridine.

EXAMPLE 3

Intra-ocular lenses were machined from lens blank formed of polymer 8 ofTable I by polymerizing a mixture of N-vinyl imidazole, 4-vinyl pyridine(25 wt %), and tetraethyleneglycol diacrylate with an AIBN initiator.The same general procedure described in Example 1 was utilized toprepare the mixture filled ampoule for polymerization and thepolymerization process also included a 48 hour cycle at 60° C. and a 24hour cycle at 120° C.

Exemplary lenses were similar in dimensions to those described inExample 2. A typical optical resolution of the exemplary lenses in thedehydrated state was 80% as measured on a Meclab optical bench. Theexemplary lenses were then deformed according to the procedures providedin Example 2. After hydration in physiologically buffered aqueoussolutions for about 24 hours, the deformed lenses recovered theiroriginal configurations. As measured on a Meclab optical bench, atypical optical resolution of 70% was found for the hydrated lenses.This compares favorably with the 60% optical resolution minimallyacceptable within the ophthalmic industry.

The following example illustrates a number of the high refractive indexhydrogels of the present invention.

EXAMPLE 4

The general procedure described in Example 1 was followed using variouscombinations of heterocyclic monomers. The results, including therefractive index, n_(D) ²⁰, of the cross-linked polymers and copolymersand the equilibrium water content of the hydrated polymers, are shown inTable III.

Those abbreviations utilized in Table III not previously identified inTable II are defined in Table IV, immediately following.

                                      TABLE III                                   __________________________________________________________________________    MONOMERS AND                                                                             POLYMERIZATION                                                     COMPONENTS CONDITIONS  PROPERTIES                                             __________________________________________________________________________    (11)                                                                          VPZ 1 g     60° C./24 h                                                                       Clear light brown solid;                               TEGDA 13 μl                                                                           120° C./12 h                                                                       clear slight yellow when                               AIBN 10 mg             swollen; water content 89.2%;                                                 n.sub.D.sup.20 (dry) = 1.594                           (12)                                                                          4VP 2 g     60° C./48 h                                                                       Clear slightly yellow solid;                           TEGDA 18 μl                                                                           120° C./24 h                                                                       clear colorless when swollen;                          AIBN 2 mg              water content 26.7%;                                                          n.sub.D.sup.20 (dry) = 1.591                           (13)                                                                          NVI 7.5 g   60° C./48 h                                                                       Clear light yellow solid;                              4VP 2.5 g  120° C./48 h                                                                       clear slightly yellow when                             TEGDA 100 μl        swollen; water content 65.6%;                          AIBN 10 mg             n.sub.D.sup.20 (dry) = 1.563                           DCP 10 mg                                                                     (14)                                                                          NVI 7.5 g   60° C./48 h                                                                       Clear slightly yellow solid;                           3VP 2.5 g  120° C./48 h                                                                       clear very slightly yellow when                        DEGDA 71 μl         swollen; water content 69.7%;                          AIBN 10 mg             n.sub.D.sup.20 (dry) = 1.560                           DCP 10 mg                                                                     (15)                                                                          MPZ 3 g     60° C./48 h                                                                       Clear brown solid; clear light                         DEGDA 49 μl                                                                           120° C./48 h                                                                       brown when swollen; water content                      AIBN 9 mg              77.1%; n.sub.D.sup.20 (dry) = 1.585                    DCP 6 mg                                                                      (16)                                                                          NVI 2.2 g   60° C./36 h                                                                       Clear yellow solid; clear light                        3VP 1.5 g  120° C./12 h                                                                       yellow when swollen; water content                     VPM 1 g                57.0%; n.sub.D.sup.20 (dry) = 1.587                    DAP 92 mg                                                                     AIBN 5 mg                                                                     (17)                                                                          NVI 1.4 g   60° C./36 h                                                                       Clear deep yellow solid; clear                         VPM 0.93 g 120° C./12 h                                                                       yellow when swollen; water content                     4VP 0.61 g             63.0%; n.sub.D.sup.20 (dry) = 1.589                    DAP 58 mg                                                                     AIBN 3 mg                                                                     (18)                                                                          NVI 1.45 g  60° C./36 h                                                                       Clear yellow solid; clear very                         VPM 1 g    120° C./12 h                                                                       slightly yellow when swollen;                          4VP 0.66 g             water content 66.5%;                                   DEGDA 61 μl         n.sub.D.sup.20 (dry) = 1.586                           AIBN 3 mg                                                                     DCP 1 mg                                                                      (19)                                                                          NVI 1.46 g  60° C./36 h                                                                       Clear deep yellow solid; clear                         VPM 1 g    120° C./12 h                                                                       yellow when swollen; water content                     4VP 0.66 g             67.9%; n.sub.D.sup.20 (dry) = 1.587                    DAP 30.5 mg                                                                   AIBN 3 mg                                                                     DCP 1 mg                                                                      (20)                                                                          NVI 1.46 g  60° C./36 h                                                                       Clear yellow solid; clear                              VPM 1 g    120° C./12 h                                                                       virtually colorless when swollen;                      4VP 0.66 g             water content 69.6%;                                   DEGDA 30.5 μl       n.sub.D.sup.20 (dry) = 1.588                           AIBN 3 mg                                                                     DCP 1 mg                                                                      (21)                                                                          VPM 944 μl                                                                             60° C./36 h                                                                       Clear light yellow solid;                              NVP 439 μl                                                                            135° C./4 h                                                                        clear virtually colorless when                         DEGDA 47.1 μl       swollen; Water content 72.0%;                          AIBN 0.8 mg            n.sub.D.sup.20 (dry) = 1.570                           DCP 0.8 mg                                                                    (22)                                                                          VPM 802 μl                                                                             60° C./36 h                                                                       Clear light yellow solid;                              NVP 780 μl                                                                            135° C./4 h                                                                        clear virtually colorless when                         4VP 291 μl          swollen; Water content 71.0%;                          DEGDA 52.3 μl       n.sub.D.sup.20 (dry) = 1.563                           AIBN 1 mg                                                                     DCP 1 mg                                                                      (23)                                                                          NVI 1236 μl                                                                            60° C./36 h                                                                       Clear light yellow solid;                              VPM 607 μl                                                                            135° C./4 h                                                                        clear virtually colorless when                         DEGDA 68.9 μl       swollen; Water content 66.0%;                          AIBN 1 mg              n.sub.D.sup.20 (dry) = 1.570                           DCP 1 mg                                                                      __________________________________________________________________________

                  TABLE IV                                                        ______________________________________                                        COMPONENTS        ABBREVIATION                                                ______________________________________                                        Vinylpyrazine     VPZ                                                         Dicumyl peroxide  DCP                                                         Diethylene glycol diacrylate                                                                    DEGDA                                                       3-Vinylpyridine   3VP                                                         2-Methyl-5-vinylpyrazine                                                                        MPZ                                                         4-Vinylpyrimidine VPM                                                         1,4-Diacryloyl piperazine                                                                       DAP                                                         ______________________________________                                    

Having thus described exemplary embodiments of the present invention, itshould be noted by those skilled in the art that the disclosures hereinare exemplary only and that alternatives, adaptations and modificationsmay be made within the scope of the present invention.

What is claimed is:
 1. A hydrogel comprising a cross-linked polymer prepared from a mixture of monomers comprising N-vinylpyrrolidone, 4-vinylpyrimidine, and a vinyl pyridine, and a cross-linking agent selected from the group consisting of diethylene glycol diacrylate, tetraethylene glycol diacrylate, and 1,4-diacryloylpiperazine.
 2. A hydrogel comprising a cross-linked polymer prepared from a mixture of monomers comprising N-vinylpyrrolidone and 4-vinylpyrimidine, and a cross-linking agent selected from the group consisting of diethylene glycol diacrylate, tetraethylene glycol diacrylate, and 1,4-diacryloylpiperazine.
 3. The hydrogel of claim 1 wherein said cross-linked polymer has a refractive index, n_(D) ²⁰, ranging from 1.560 to 1.594 in the dry state.
 4. The hydrogel of claim 2 wherein said cross-linked polymer has a refractive index n_(D) ²⁰, ranging from 1.560 to 1.594 in the dry state.
 5. The hydrogel of claim 3 wherein said cross-linked polymer has a hydrated equilibrium water content of about 57% to 90%.
 6. The hydrogel of claim 4 wherein said cross-linked polymer has a hydrated equilibrium water content of about 57% to 90%. 